PROJECT SUMMARY Drug addiction is characterized by pervasive neurocognitive impairments that exacerbate and maintain the illness. These impairments are observed in basic, first-order domains, such as working memory, sustained attention, and decision-making, but also in second-order awareness regarding the severity of the first-order deficits (i.e., metacognition: ?thinking about thinking?). Importantly, (second-order) metacognition deficits can be conceptually and empirically disentangled from the basic (first-order) deficits, suggesting the involvement of at least partly distinct brain circuits and molecular underpinnings, and perhaps a complementary contribution to the prediction of drug use. In this R21 application, we probe for the first time the neural circuitry of metacognition in drug (opioid) addiction, and link deficits in this circuitry to a novel neurochemical mechanism: functioning of the noradrenergic system (which notably is also implicated in key addiction symptomatology, such as withdrawal). Individuals with opioid use disorder (OUD) (specifically who are users of heroin; methadone-maintained) and matched healthy controls (HC) will complete a functional magnetic resonance imaging (fMRI) metacognition task, previously validated in HC, but here extended for the first time to OUD. Behavioral evidence of metacognitive impairment in OUD has started to emerge, but this will be the first examination of the underlying circuitry. During the fMRI task, participants report their confidence in their ongoing task accuracy, with metacognition then operationalized as the positive correlation between higher confidence and better performance. The fMRI analyses examine the trial-by-trial correlation between confidence ratings and brain activation, with parametric signals expected to emerge in the lateral prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Eye-tracking is used throughout the task to collect information on pupil dilation, a recognized marker of locus coeruleus (LC)- norepinephrine engagement. Pupil dilation as a marker of noradrenergic function is supplemented by neuromelanin-sensitive MRI in the LC, an innovative marker of the lifetime cumulative breakdown of catecholamines including norepinephrine, which may show an abnormal signal in addiction due to chronic drug exposure and its effects on the noradrenergic system. Specific Aims include testing for group differences between OUD and HC in metacognition behavior and neural function, and relating the extent of the metacognition-related abnormalities to measures of noradrenergic functioning and drug use severity. If the anticipated relationships are observed, our results will shed light on a novel neurocognitive deficit in addiction that has the potential to perpetuate drug use. Positive results will also suggest a novel neurochemical mechanism of the impairment, which may be amenable to intervention via noradrenergic therapeutics. Thus, our proposal is a necessary first step, consistent with the R21 mechanism, that will establish a foundation in this field and provide the impetus for larger investigations.